Human immunodeficiency virus (HIV) associated neurocognitive disorder (HAND) represents a major chronic health problem in the US and abroad. MRI studies of HAND consistently show a decrease in the size of the hippocampus and other brain structures associated with learning and memory. Advances in treatment of HAND have been made by administering brain derived neurotrophic factor (BDNF) directly to the CNS, or by using drugs that can increase BDNF indirectly. BDNF promotes neuronal plasticity and restores brain functions. However, BDNF cannot cross an intact blood brain barrier (BBB), and is unstable in the blood or when delivered orally. The goal of this effort is to produce non-toxic, BDNF-nanoparticles, and to test the hypothesis that these nanoprobes bypass the BBB intranasally, target BDNF receptor rich brain regions, and prevent or reverse neurotoxic effects of HIV transactivator of transcription (tat) protein in a mouse model relevant to HAND, the GT-tg bigenic mouse induced with doxycycline to overexpress tat protein. To accomplish these goals we will design a two-part nanoprobe (<50 nanometers). A nanocarrier will be constructed out of clathrin, a naturally occurring protein the body uses for transporting molecules into cells. The second component will be a BDNF protein drug. BDNF will be attached to polyethylene glycol (PEG) molecules coating the carrier. A series of studies will ascertain the affinity, specificity ad functionality of the nanoprobes in vivo. We plan to demonstrate the feasibility of this novel nanotechnology to prevent and treat tat neurotoxicity associated with HAND. If this research project is successful it will provide new noninvasive nanotechnology tools for prevention and treatment of neurotoxicity that may be useful for treating HAND. The new nanotechnology may be able to enhance neuronal plasticity and restore brain functions more quickly and completely than existing treatment methods, while using much lower therapeutic drug doses and causing fewer side effects. The development of a stable, targeted molecular nanoprobe may also provide a major new tool for research of molecular abnormalities in HAND and co-morbid disorders. This novel nanotechnology may serve as the basis for a next generation drug-delivery system that can specifically target relevant brain systems, and also may have utility as an imaging agent to enhance diagnosis and monitor progression of the disease.